Inhibited Tumor Cell Proliferation Research Articles

Photothermal Responsive Microcarriers Encapsulated With Cangrelor and 5-Fu for Colorectal Cancer Treatment.

Localized chemotherapy is emerging as a potential strategy for cancer treatment due to its low systemic toxicity. However, the immune evasion of tumor cells and the lack of an intelligent design of the delivery system limit its clinical application. Herein, photothermal responsive microcarriers are designed by microfluidic electrospray for colorectal tumor treatment. The microcarriers loaded with Cangrelor, 5-FU and MXene (G-M@F/C+NIR) show sustained delivery of antiplatelet drug Cangrelor, thus inhibiting the activity of platelets, interactions of platelet-tumor cell, as well as the tumor cells invasion and epithelial-mesenchymal transition (EMT). In addition, the sustained delivery of chemotherapeutics 5-FU and the photothermal effect provided by MXene enable the microcarriers to inhibit tumor cells proliferation and migration. In vivo studies validate that the G-M@F/C+NIR microcarriers significantly inhibites tumor growth, decreased the expression of Ki-67 in tumor cells and vascular endothelial growth factor (VEGF) in the tumor microenvironment, while increased the expression of E-cadherin. It is believe that by means of the proposed photothermal responsive microcarriers, the synergistic strategy of platelet inhibition, chemotherapy, and photothermal therapy can find practical applications in cancer treatment.

Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer.

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon (IFN) response uniformly across models. The induction of an IFN response is partially due to the inhibition of Sox4 translation by zotatifin. A similar induction of IFN-stimulated genes was observed in breast cancer patient biopsies following zotatifin treatment. Surprisingly, zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened IFN response, resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for zotatifin, and provide a rationale for new combination regimens consisting of zotatifin and chemotherapy or immunotherapy as treatments for TNBC.

10168-BOT-2 ANTITUMOR AROMA THERAPY WITH LEMONGRASS ESSENTIAL OIL FOR GLIOBLASTOMA

Abstract Aromatic essential oils have been used in cancer treatment to enhance immunity, induce sedation, and reduce the side effects of chemotherapy. Recently, essential oils have been reported to have anti-tumor effects. We have been investigating anti-tumor aroma of essential oils as a novel treatment for glioblastoma and have found that hiba essential oil has a proliferation inhibitory effect. In this study, we investigated the antitumor effect of lemongrass essential oil for glioblastoma and its antitumor aromatherapy. Human glioblastoma cells (U87, T98G) and mouse brain tumor cells (RSV-M) were used. Lemongrass essential oil was added to each tumor cell line, and growth inhibition was observed in all cell lines. In addition, lemon grass essential oil showed growth inhibition effect when the tumor cells were separated from the oil, as was the case with direct administration, suggesting that the lemongrass essential oil components that evaporated acted on tumor cells in the surrounding area. The antitumor component of lemongrass essential oil was isolated and identified as citral, an antitumor factor, by gas chromatography. Analysis of the effects of citral showed that it strongly inhibited MARK4 activity and growth in three cell lines. The mechanism revealed that citral decreased the phosphorylation of Tau protein. MARK4 is highly expressed in glioblastoma and has been reported to be involved in cell proliferation. This study suggests a potential mechanism for citral to inhibit tumor cell proliferation via MARK4 in malignant gliomas. Citral is a volatile monoterpene and may exert its antitumor effect by evaporation diffusion. Lemongrass essential oil contains citral, which shows antitumor effects, and is expected to be applied to a new glioblastoma therapy using "aroma".

The Emerging Roles of the Metabolic Regulator G6PD in Human Cancers.

Metabolic reprogramming, especially reprogrammed glucose metabolism, is a well-known cancer hallmark related to various characteristics of tumor cells, including proliferation, survival, metastasis, and drug resistance. Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway (PPP), a branch of glycolysis, that converts glucose-6-phosphate (G6P) into 6-phosphogluconolactone (6PGL). Furthermore, PPP produces ribose-5-phosphate (R5P), which provides sugar-phosphate backbones for nucleotide synthesis as well as nicotinamide adenine dinucleotide phosphate (NADPH), an important cellular reductant. Several studies have shown enhanced G6PD expression and PPP flux in various tumor cells, as well as their correlation with tumor progression through cancer hallmark regulation, especially reprogramming cellular metabolism, sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Inhibiting G6PD could suppress tumor cell proliferation, promote cell death, reverse chemoresistance, and inhibit metastasis, suggesting the potential of G6PD as a target for anti-tumor therapeutic strategies. Indeed, while challenges-including side effects-still remain, small-molecule G6PD inhibitors showing potential anti-tumor effect either when used alone or in combination with other anti-tumor drugs have been developed. This review provides an overview of the structural significance of G6PD, its role in and regulation of tumor development and progression, and the strategies explored in relation to G6PD-targeted therapy.

The mechanism and application of traditional Chinese medicine extracts in the treatment of lung cancer and other lung-related diseases.

Lung cancer stands as one of the most prevalent malignancies worldwide, bearing the highest morbidity and mortality rates among all malignant tumors. The treatment of lung cancer primarily encompasses surgical procedures, radiotherapy, and chemotherapy, which are fraught with significant side effects, unfavorable prognoses, and a heightened risk of metastasis and relapse. Although targeted therapy and immunotherapy have gradually gained prominence in lung cancer treatment, diversifying the array of available methods, the overall recovery and survival rates for lung cancer patients remain suboptimal. Presently, with a holistic approach and a focus on syndrome differentiation and treatment, Traditional Chinese Medicine (TCM) has emerged as a pivotal player in the prognosis of cancer patients. TCM possesses characteristics such as targeting multiple aspects, addressing a wide range of concerns, and minimizing toxic side effects. Research demonstrates that Traditional Chinese Medicine can significantly contribute to the treatment or serve as an adjunct to chemotherapy for lung cancer and other lung-related diseases. This is achieved through mechanisms like inhibiting tumor cell proliferation, inducing tumor cell apoptosis, suppressing tumor angiogenesis, influencing the cellular microenvironment, regulating immune system function, impacting signal transduction pathways, and reversing multidrug resistance in tumor cells. In this article, we offer an overview of the advancements in research concerning Traditional Chinese Medicine extracts for the treatment or adjunctive chemotherapy of lung cancer and other lung-related conditions. Furthermore, we delve into the challenges that Traditional Chinese Medicine extracts face in lung cancer treatment, laying the foundation for the development of diagnostic, prognostic, and therapeutic targets.

Construction and performance evaluation of pH-responsive oxidized hyaluronic acid hollow mesoporous silica nanoparticles

In this study, hollow mesoporous silica (HMSN) was created to facilitate drug distribution using the hard template method. The oxidized hyaluronic acid (oxiHA) was coated on the carrier surface by the Schiff base reaction, producing the pH-responsive nanoparticles HMSNs-DOX-oxiHA targeted by CD44 and preventing drug leakage from mesopores. The prepared nanoparticles had a size of 151.79 ± 13.52 nm and a surface potential of −8.42 ± 0.48 mV. The rich mesoporous structure and internal cavity of HMSNs-NH2 achieved the effective encapsulation and loading rates of doxorubicin (DOX) at 76.84 ± 0.24 % and 18.73 ± 0.05 %, respectively. Owing to the pH sensitivity of imine bonds, HMSNs-DOX-oxiHA has a good pH response and release performance. The in vitro experiments showed that the nanoparticles were not cytotoxic and could enhance HCT-116 uptake efficiency by hyaluronic acid/CD44 receptor-mediated endocytosis, effectively inhibiting tumor cell proliferation and reducing toxic side effects on normal cells. In summary, the polysaccharide-based nano-drug delivery system constructed in this experiment not only has the basic response properties of a carrier but also introduces the bioactive advantages of natural polysaccharides.

Regulating miRNAs Expression by Resveratrol: Novel Insights based on Molecular Mechanism and Strategies for Cancer Therapy.

Resveratrol, a polyphenolic phytoalexin found in a wide range of plants, including grapes, berries, and peanuts, is an extensively researched phytochemical with unique pharmacological capabilities and amazing potential to affect many targets in various cancers. Resveratrol's anti-cancer activities are due to its targeting of a variety of cellular and molecular mechanisms and crucial processes involved in cancer pathogenesis, such as the promotion of growth arrest, stimulation of apoptosis, suppression of cell proliferation, induction of autophagy, regulating oxidative stress and inflammation, and improving the influence of some of the other chemotherapeutic agents. MicroRNAs (miRNAs) are non-coding RNAs that modulate gene expression by degrading mRNA or inhibiting translation. MiRNAs serve critical roles in a wide range of biological activities, and disruption of miRNA expression is strongly linked to cancer progression. Recent research has shown that resveratrol has anti-proliferative and/or pro-apoptotic properties via modulating the miRNA network, which leads to the inhibition of tumor cell proliferation, the activation of apoptosis, or the increase of traditional cancer therapy effectiveness. As a result, employing resveratrol to target miRNAs will be a unique and potential anticancer approach. Here, we discuss the main advances in the modulation of miRNA expression by resveratrol, as well as the several miRNAs that may be influenced by resveratrol in different types of cancer and the significance of this natural drug as a promising strategy in cancer treatment.

Hsa-miR-548k blocks the drug resistance cascade in NSCLC cancer by targeting the key genes involved in various chemotherapy resistance pathways

Although new therapeutic approaches have been developed, and efforts have been made to understand cancer signaling pathways, drug resistance remains the most common cause of tumor recurrence and therapy. microRNAs degrade mRNAs or target their specific sequences as translation repressors. miRNA disruption may alter the drug sensitivity of cancer cells and influence tumor cell resistance to chemotherapy. Modulation of miRNAs through antagomiRs or mimics inhibit tumor cell proliferation and enhance drug sensitivity by regulating critical gene networks and signaling pathways. miRNAs that simultaneously involve the 3′-UTR of genes responsible for various drug resistance pathways in lung cancer were identified with the miRvestigator algorithm. Its validity was confirmed with TargetScan and the expression level of introduced genes was investigated under the influence of its mimic. Finally, the percentage of viable cells was determined using the apoptosis assay. Hsa-miR-548k was identified as a potential gene regulator of multiple drug resistance signaling in lung cancer using miRvestigator bioinformatics algorithms. Hsa-miR-548k mimics were transiently transfected into A549 cells to investigate the effect of hsa-miR-548k on the expression of ATP-binding cassette super-family G member 2 (ABCG2), epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), Yes1 Associated Transcriptional Regulator (YAP), and vascular endothelial growth factor (VEGF). Quantitative analyses confirmed significant downregulation of the gene expression levels involved in lung cancer drug resistance pathways by hsa-miR-548k. Furthermore, hsa-miR-548k overexpression increased the apoptosis of A549 cells. This study not only confirmed the significance of hsa-miR-548k in regulating drug resistance pathways but also identified it as a new target for the treatment of lung cancer.

MicroRNA-299-3p inhibits cell proliferation, motility, invasion and angiogenesis via VEGFA in upper tract urothelial carcinoma.

Upper tract urothelial carcinoma (UTUC) is a rare tumor with extraordinarily different features between Eastern and Western countries. Vascular endothelial growth factor-A (VEGFA) was originally identified as a secreted signaling protein and regulator of vascular development and cancer progression. In this study, we aimed to elucidate the molecular mechanisms underlying the regulation of VEGFA by microRNA in UTUC. VEGFA expression was evaluated by immunohistochemistry in 140 human UTUC tissue samples. Next, we assessed the regulatory relationship between VEGFA and miR-299-3p by real-time PCR, western blotting, ELISA and dual-luciferase reporter assays using two UTUC cell lines. The role of miR-299-3p/VEGFA in cell proliferation, motility, invasion, and tube formation was analyzed in vitro. High VEGFA expression was significantly associated with tumor stage, grade, distant metastasis and cancer-related death and correlated with poor progression-free and cancer-specific survival. VEGFA knockdown repressed proliferation, migration, invasion and angiogenesis in UTUC cell lines. miR-299-3p significantly reduced VEGFA protein expression and miR-299-3p overexpression inhibited VEGFA mRNA and protein expression by directly targeting its 3'-UTR. Functional studies indicated that VEGFA overexpression reversed the miR-299-3p-mediated suppression of tumor cell proliferation, migration, invasion and angiogenesis. In addition, miR-299-3p/VEGFA suppressed cellular functions in UTUC by modulating the expression of P18 and cyclin E2. Our findings suggest that miR-299-3p possibly suppresses UTUC cell proliferation, motility, invasion and angiogenesis via VEGFA. VEGFA may act as a prognostic predictor, and both VEGFA and miR-299-3p could be potential therapeutic targets for UTUC.

IDO2-siRNA Carried by Salmonella Combined with Nifuroxazide Attenuates Melanoma Growth.

Melanoma, a highly malignant skin cancer, is a hot topic in oncology treatment research. Nowadays, tumor immunotherapy, especially immunotherapy combined with other therapies, has attracted more and more attention. Indoleamine 2,3-dioxygenase 2 (IDO2), a ratelimiting enzyme of the tryptophan metabolism pathway in the urine of dogs with immunosuppression, is highly expressed in melanoma tissue. Additionally, IDO2 significantly inhibits the anti-tumor immunity of the body and has become a novel target of melanoma treatment. Nifuroxazide, as an intestinal antibacterial agent, was found to be able to inhibit Stat3 expression and exert an anti-tumor effect. Therefore, the present study aimed to examine the therapeutic effect of a self-designed IDO2-small interfering RNA (siRNA) delivered by attenuated Salmonella combined with nifuroxazide on melanoma- bearing mice, as well as determine its underlying mechanism. The effect of nifuroxazide on melanoma was detected by flow cytometry, CCK-8 and colony- forming ability assays, respectively, in vitro. The plasmid of siRNA-IDO2 was constructed, and the mice-bearing melanoma model was established. After the treatment, the tumor growth and survival rate were monitored, and the morphological changes of tumor tissue were detected by HE staining. The expression of related proteins was detected by Western blotting, and the expression of CD4 and CD8 positive T cells in tumor tissue was detected by IHC and IF, and the proportion of CD4 and CD8 positive T cells in spleen was detected by flow cytometry. The results demonstrated that the combination therapy effectively inhibited the phosphorylation of Stat3 and the expression level of IDO2 in melanoma cells, which effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice. The mechanistic study revealed that, compared with control groups and monotherapy groups, the combination treatment group reduced the atypia of tumor cells, increased the apoptotic rate, enhanced the infiltration of T lymphocytes in tumor tissue and increased the CD4+ and CD8+ T lymphocytes in the spleen, suggesting that the mechanism may be associated with the inhibition of tumor cell proliferation, the increase of apoptosis and the enhancement of the cellular immunity. In conclusion, IDO2-siRNA combined with nifuroxazide therapy could serve a significant role in the treatment of melanoma-bearing mice, enhance the tumor immunity and provide an experimental basis for identifying a novel combination method for the treatment of melanoma clinically.

Abstract C129: Development of new increased potency Ref-1/APE1 targeted inhibitors that show promise for clinical applications against solid tumors

Abstract AP endonuclease-1/Redox factor-1 (APE1/Ref-1 or Ref-1) is a multifunctional protein that is over-expressed in most aggressive cancers and impacts various cancer cell signaling pathways. Among its primary functions, Ref-1’s redox activity plays a significant role in activating transcription factors (TFs) such as NFkB, HIF1a, and AP-1, among others, which are crucial contributors to the development of tumors and metastatic growth. Therefore, development of potent, selective inhibitors to target Ref-1 redox function is an appealing approach for therapeutic intervention. A first-generation compound, APX3330 successfully completed phase I clinical trial in adults with progressing solid tumors with favorable response rate, pharmacokinetics (PK), and minimal toxicity. These positive results prompted us to develop even more potent analogs of APX3330 to effectively target Ref-1 in solid tumors. In this study, we present structure-activity relationship (SAR) identification and validation of more potent lead compounds that exhibit a similar/better safety profile to APX3330. Pharmacokinetics, mouse and human S9 fraction metabolic stability, in silico ADMET properties, ligand-based WaterLOGSY NMR measurements, TF-driven luciferase activity, and two 3-dimensional (3D) cell killing assays (interstitial Tumor-Microenvironment (TME) on a Chip and 3D spheroid) were used for inhibitor characterization. These efforts have elucidated five compounds with improved PK, target engagement, and increased efficacy for cell killing compared to parent compound. Ligand-based WaterLOGSY NMR measurements demonstrate direct interaction of these inhibitors with Ref-1. Target inhibition was further confirmed following Ref-1 treatment via reporter assay with significant and dose-dependent decreases in TF-driven luciferase activity (3-6-fold compared to APX3330). In two 3D co-culture models, second-generation Ref-1 redox analogs suppressed tumor survival significantly with significantly increased potency (~10-fold) compared to APX3330. APX2014, 44, and 51 also inhibited tumor cell proliferation more dramatically (1.5-3.5-fold) than cancer-associated fibroblasts from the TME. Two compounds, APX2044 and 51 outperformed the other analogs as well as the parent compound as assessed by inhibition of downstream TFs regulated by Ref-1 activity, inhibition of mitochondrial metabolism, greater potency against tumors than CAFs in monolayer and in 3D co-culture experiments. PK studies also demonstrated that efficacious doses are clinically achievable for these new inhibitors. Additionally, these findings have allowed us to develop additional analogs for further refinement. Thus, our preclinical findings identified more potent inhibitors of Ref-1 redox function (5-10-fold more than APX3330) that can be translated to the clinic. This study provides invaluable information regarding new Ref-1 analogs for advancement to in vivo and eventual IND-enabling studies and demonstrates the effectiveness of these compounds in sophisticated in vitro models in cancers that are in need of therapeutic options. Citation Format: Silpa Gampala, Hye-Ran Moon, Randall Wireman, Jacqueline Peil, Sonia Kiran, Andi Masters, Christine Bach, Whitney Smith-Kinnamen, Emma Doud, Ratan Rai, Amber L Mosley, Millie M Georgiadis, Bumsoo Han, Chi Zhang, Chafiq Hamdouchi, James Wikel, Mark R Kelley, Melissa L Fishel. Development of new increased potency Ref-1/APE1 targeted inhibitors that show promise for clinical applications against solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C129.

Ubiquitin-Mediated Degradation of MORF4L1 By FBXO11 Suppresses Cholesterol Biosynthesis in T Cell Acute Lymphoblastic Leukemia

The substrate receptor of SKP1-Cullin1-FBOX complex, FBXO11, is frequently mutated in both diffuse large B cell lymphoma and acute myeloid leukemia, and typically functions as a tumor suppressor by targeting substrates for ubiquitin-mediated degradation. Although FBXO11 is also mutated in human T-cell acute lymphoblastic leukemia (T-ALL) cell lines, the underlying mechanism in T-ALL development remains to be established. Here, we identified that both endogenous activation and exogenous overexpression of FBXO11 could suppress the growth of T-ALL cell in vitro and in vivo. While conversely, loss of FBXO11 accelerates the T-ALL cell proliferation. Transcriptomic and total quantitative proteomic analyses in FBXO11-depleted T-ALL cells reveal activation of the cholesterol biosynthesis pathway with accumulation of intracellular cholesterol levels. Importantly, we identified a chromatin regulator MORF4L1, mortality factor 4 like protein 1, as a functional substrate of FBXO11 in T-ALL cells. We first observed that FBXO11 exhibited frequent copy number alterations in T-ALL cell lines and in patient cohorts from public datasets. Moreover, by CRISPR SAM (Synergistic Activation Mediator) endogenous activation and lentiviral mediated gene overexpression, we validated that FBXO11 played a role in inhibiting tumor cell proliferation in T-ALL cells both in vitro and in vivo. Conversely, loss of FBXO11 accelerated T-ALL cell proliferation. Taken together, our results suggest that FBXO11 functions as a tumor suppressor in T-ALL. Mechanistically, we uncovered that the absence of FBXO11 could activate the cholesterol synthesis signaling pathway from both the RNA-seq and the TMT proteomic analysis in FBXO11-depleted MOLT4 cells compared to control cells. Concordantly, loss of FBO11 resulted in the accumulation of intracellular cholesterol level, suggesting that FBXO11 may suppress cholesterol biosynthesis in T-ALL cells. To understand how FBXO11 controls cholesterol biosynthesis, we further identified the potential substrates from the combined quantitative transcriptome and proteome analysis. MORF4L1, a chromatin modifier involved in histone acetylation, was identified as a key substrate of FBXO11 based on its upregulation at the protein level in FBXO11-depleted cells. Moreover, our data suggest MORF4L1 is a regulator of cholesterol biosynthesis in T-ALL. The inhibition of MORF4L1 suppressed the cellular growth of T-ALL cell lines, and led to the downregulation of the expression of cholesterol-related genes, such as gene HMGCR and HMGCS1. Of note, suppression of MORF4L1 and its cholesterol biosynthesis target genes such as HMGCR, HMGCS1 could rescue the accelerated growth effect after loss of FBXO11, indicating a functional role for MORF4L1 in T-ALL development. In summary, our data support a model wherein the degradation of MORF4L1 by FBXO11 suppresses leukemia cell growth by controlling cholesterol biosynthesis. The identification of this regulatory mechanism is required for T-ALL and provides valuable insights into the metabolic vulnerabilities of leukemia.

Biocompatible Ferrofluid-Based Millirobot for Tumor Photothermal Therapy in Near-Infrared-II Window.

Ferrofluidic robots with excellent deformability and controllability have been intensively studied recently. However, most of these studies are in vitro and the use of ferrofluids for in vivo medicinal applications remains a big challenge. The application of ferrofluidic robots to the body requires the solution of many key problems. In this study, biocompatibility, controllability, and tumor-killing efficacy are considered when creating a ferrofluid-based millirobot for in vivo tumor-targeted therapy. For biocompatibility problems, corn oil is used specifically for the ferrofluid robot. In addition, a control system is built that enables a 3D magnetic drive to be implemented in complex biological media. Using the photothermal conversion property of 1064nm, the ferrofluid robot can kill tumor cells in vitro; inhibit tumor volume, destroy the tumor interstitium, increase tumor cell apoptosis, and inhibit tumor cell proliferation in vivo. This study provides a reference for ferrofluid-based millirobots to achieve targeted therapies in vivo.

Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant digestive tract tumor with limited clinical treatments. Transforming acidic coiled-coil-containing protein 3 (TACC3) is a component of the centrosome axis and a member of the TACC family, which affect mitosis and regulate chromosome stability and are involved in tumor development and progression. However, the role of TACC3 in PDAC remains elusive. In this study, by exploiting the TCGA database, we found that high TACC3 expression in PDAC is associated with poor prognosis. shRNA-mediated TACC3 knockdown caused S phase arrest of the cell cycle and inhibited proliferation in PDAC cell lines. Through RNA sequencing and protein co-immunoprecipitation combined with mass spectrometry, KIF11 was identified as a protein that interacts with TACC3. TACC3 stabilizes and regulates KIF11 protein expression levels in PDAC cells through physical interaction. Knockdown of TACC3 or KIF11 resulted in abnormal spindle formation during cell division both in vitro and in vivo. Pharmacological inhibition of TACC3 or KIF11 can suppress tumor cell proliferation and promote apoptosis. Our studies further demonstrated that high expression of TACC3 and KIF11 mediated the resistance of PDAC to gemcitabine, and deficiency of TACC3 or KIF11 increased the sensitivity of PDAC cells to chemotherapy. In conclusion, our study reveals the fundamental role of TACC3 expression in PDAC cell proliferation and chemoresistance, suggesting that TACC3 can be used as a molecular marker to evaluate the prognosis of PDAC.

Synthesis and evaluation of small molecule-based derivatives as inhibitors of polo-box domain of polo-like kinase-1

ObjectivesPolo-like kinase 1 (Plk1) is an important mitotic protein. In particular, this protein is highly overexpressed in many types of tumors and has been identified as a potential biomarker for the treatment and diagnosis of tumors. Plk1 is composed of two domains, an N-terminal kinase domain and a C-terminal polo-box domain (PBD). Presently, inhibitors with improved selectivity and specificity for Plk1 are unavailable. Therefore, we aimed to develop an inhibitor targeting the C-terminal PBD present only in Plk1.Methods & resultsIn this study, three derivatives targeting PBD for Plk1 were designed by protein–protein interactions, which showed high levels of selectivity and specificity for Plk1 PBD, and were evaluated to inhibit tumor cell proliferation through an apoptotic process during tumor cell division. The investigation of the in vitro and in vivo antitumor effects of these inhibitors demonstrated that one of the new small molecules, 1, is a promising anticancer agent.ConclusionOur findings can provide new insights for the design of novel Plk1 peptide inhibitors in the future.

Anticancer effect of superoxide dismutase on canine mammary gland tumour in vitro.

Reactive oxygen species (ROS) have been shown to promote tumour growth and metastasis in human cell lines. The superoxide anion (•O2 - ) is produced during ROS formation and is involved in tumour cell signalling. Superoxide dismutase (SOD) has been applied to canine mammary gland tumours to investigate its antitumour effects in vitro. Cell proliferation, cell cycle cell migration assays, reverse transcription-quantitative polymerase chain reaction, and western blot analysis were performed to determine the effects of SOD on canine mammary tumour cell line. SOD treatment resulted in anti-proliferative effects and mediated cell cycle arrest in the canine mammary gland tumour cell lines (CIPp and CIPm). It also downregulated the expression of N-cadherin and Vimentin. The results confirmed that SOD inhibits tumour cell proliferation and migration, thus supporting the potential applications of SOD as a chemotherapeutic agent for canine mammary gland tumours.

Elucidation of GPR55-Associated Signaling behind THC and LPI Reducing Effects on Ki67-Immunoreactive Nuclei in Patient-Derived Glioblastoma Cells.

GPR55 is involved in many physiological and pathological processes. In cancer, GPR55 has been described to show accelerating and decelerating effects in tumor progression resulting from distinct intracellular signaling pathways. GPR55 becomes activated by LPI and various plant-derived, endogenous, and synthetic cannabinoids. Cannabinoids such as THC exerted antitumor effects by inhibiting tumor cell proliferation or inducing apoptosis. Besides its effects through CB1 and CB2 receptors, THC modulates cellular responses among others via GPR55. Previously, we reported a reduction in Ki67-immunoreactive nuclei of human glioblastoma cells after GPR55 activation in general by THC and in particular by LPI. In the present study, we investigated intracellular mechanisms leading to an altered number of Ki67+ nuclei after stimulation of GPR55 by LPI and THC. Pharmacological analyses revealed a strongly involved PLC-IP3 signaling and cell-type-specific differences in Gα-, Gβγ-, RhoA-ROCK, and calcineurin signaling. Furthermore, immunochemical visualization of the calcineurin-dependent transcription factor NFAT revealed an unchanged subcellular localization after THC or LPI treatment. The data underline the cell-type-specific diversity of GPR55-associated signaling pathways in coupling to intracellular G proteins. Furthermore, this diversity might determine the outcome and the individual responsiveness of tumor cells to GPR55 stimulation by cannabin oids.

A versatile strategy to construct surface functionalized pH/redox dual stimuli‐responsive nanogels for targeted drug delivery

AbstractDeveloping facile, green, and efficient synthetic methodology for preparing surface‐functionalized nanogels has attracted tremendous attention in the field of polymer chemistry and biomaterials engineering. Herein, a series of “clickable” P(MAA‐PMA) nanogels with reactive alkyne groups were conveniently prepared by “one‐pot” reflux‐precipitation polymerization (RPP), their particle sizes and zeta potentials are solid content‐dependent. Using P(MAA‐PMA)‐1 nanogels as the model, the physicochemical properties including particle size, surface potential, morphology, solution stability, and pH/redox responsiveness were characterized in detail. Moreover, the pH/redox dual‐responsive drug release feature/kinetics and parameters were analyzed using Korsmeyer–Peppas model and Gallagher–Corrigan model. Then the surface of nanogels was facilely modified with various thiol‐containing functional ligands via thiol‐yne photo click reaction. As targeted drug carriers, doxorubicin (DOX)‐loaded folic acid (FA)‐functionalized nanogels (FA@Nanogels/DOX) demonstrated higher tumor cell proliferation inhibition effect in B16F10 cancer cells than that in CHO‐K1 normal cells, while the non‐FA‐functionalized counterparts (Nanogels/DOX) do not show similar effect. This work provides a versatile “one‐pot RPP‐photo Click functionalization” strategy to construct surface‐functionalized pH/redox dual responsive nanogels for efficient and targeted drug delivery.

Effects of Resveratrol on Mouse B16 Melanoma Cell Proliferation through the SHCBP1-ERK1/2 Signaling Pathway.

Melanoma originates from the malignant mutational transformation of melanocytes in the basal layer of the epidermal layer of the skin. It can easily spread and metastasize in the early stage, resulting in a poor prognosis. Therefore, it is particularly important to find effective antitumor adjuvant drugs to inhibit the occurrence and development of melanoma. In this study, we found that resveratrol, a polyphenolic compound from grape plants, can significantly inhibit the proliferation, colony formation and migration of mouse melanoma B16 cells. Notably, resveratrol was also found to inhibit the expression of SHCBP1 in B16 cells. Transcriptional analysis and cellular studies showed that SHCBP1 can activate the MAPK/ERK signaling pathway to regulate cyclin expression and promote the G1/S phase transition of the cell cycle by upregulating ERK1/2 phosphorylation levels. Resveratrol further downregulates the phosphorylation level of ERK1/2 by inhibiting SHCBP1 expression, thus inhibiting tumor cell proliferation. In conclusion, resveratrol inhibits the proliferation of B16 cells by regulating the ERK1/2 signaling pathway through SHCBP1. As an upstream protein of the ERK1/2 signaling pathway, SHCBP1 may be involved in the process of resveratrol-mediated inhibition of tumor cell proliferation.

Entecavir: A Review and Considerations for Its Application in Oncology.

Entecavir (ETV) is a drug used as a first-line treatment for chronic hepatitis B (CHB) virus infection because it is a guanosine nucleoside analogue with activity against the hepatitis B virus polymerase. The ETV dosage can range from 0.5 mg to 1 mg once a day and the most common side effects include headache, insomnia, fatigue, dizziness, somnolence, vomiting, diarrhea, nausea, dyspepsia, and increased liver enzyme levels. In addition to its conventional use, ETV acts as an inhibitor of lysine-specific demethylase 5B (KDM5B), an enzyme that is overexpressed in breast, lung, skin, liver, and prostate tumors and is involved in the hormonal response, stem cell regeneration, genomic stability, cell proliferation, and differentiation. The KDM5B enzyme acts as a transcriptional repressor in tumor suppressor genes, silencing them, and its overexpression leads to drug resistance in certain tumor types. Furthermore, the literature suggests that KDM5B activates the PI3K/AKT signaling pathway, while reducing KDM5B expression decreases AKT signaling, resulting in decreased tumor cell proliferation. In silico studies have demonstrated that ETV can inhibit tumor cell proliferation and induce apoptosis by reducing KDM5B expression. ETV also appears to inhibit PARP-1, has a high genetic barrier, reducing the chance of resistance development, and can also prevent the reactivation of the hepatitis B virus in cancer patients, which have proven to be significant advantages regarding its use as a repurposed drug in oncology. Therefore, ETV holds promise beyond its original therapeutic indication.